The cytoplasmic lipid chaperons or fatty acid binding proteins (FABP), common to macrophages and adipocytes, have a central role in obesity associated insulin resistance and atherosclerosis. The long-term goal of this application is to elucidate the molecular mechanisms of FABPs in the pathogenesis of atherosclerosis and diabetes. The broad objective is to delineate lipid mediated signal transduction pathways mediating the downstream effects of FABPs. In this study we propose to study FABP actions in macrophages based on the findings from previous studies that macrophage-specific FABP, and not systemic effects of FABPs, is the predominant contributor to atherosclerosis. The specific hypothesis is macrophage stress responses to lipotoxic stress are mediated by FABPs. This is based on our exploratory work which revealed induction of endoplasmic reticulum stress response by lipotoxic stress requires the adipocyte/ macrophage fatty acid binding protein, aP2. The specific aims in this application are : (1) Determine the role of fatty acid binding proteins in mediating lipotoxicity associated ER stress response and apoptosis in macrophages and in atherosclerotic lesions, in vivo. I will analyze induction of ER stress and apoptosis upon exposure lipotoxic stress, affected via fatty acid or free cholesterol loading, in FABP deficient and FABP reconstituted macrophages. Also, I will determine the extent of ER stress and macrophage apoptosis occurring in lesions in FABP deficient mice in the apoE deficient background. (2) Determine the role of fatty acid binding proteins in lipid mediated pro-survival signal transduction. I will analyze activation of several fatty acid or cholesterol sensing signal transduction pathways, namely AMPK/ mTOR/s6K1 and PPAR/LXR, in FABP deficient and FABP reconstituted macrophages. (3) Determine the contribution of PPAR and LXR to FABP deficiency associated alterations in macrophage biology and protection from atherosclerosis and insulin resistance in vivo. This aim will be achieved by analyzing macrophages and mice that are double deficient for FABP and PPAR or FABP and LXR. The mechanistic insight gained from these studies could lead to specific therapeutic targets for treatment of obesity related diseases such as atherosclerosis and diabetes, which are major public health concerns.